Exploring mechanisms of action in clinical trials of complex surgical interventions using mediation analysis.

BACKGROUND: Surgical interventions allow for tailoring of treatment to individual patients and implementation may vary with surgeon and healthcare provider. In addition, in clinical trials assessing two competing surgical interventions, the treatments may be accompanied by co-interventions. AIMS: This study explores the use of causal mediation analysis to (1) delineate the treatment effect that results directly from the surgical intervention under study and the indirect effect acting through a co-intervention and (2) to evaluate the benefit of the surgical intervention if either everybody in the trial population received the co-intervention or nobody received it. METHODS: Within a counterfactual framework, relevant direct and indirect effects of a surgical intervention are estimated and adjusted for confounding via parametric regression models, for the situation where both mediator and outcome are binary, with baseline stratification factors included as fixed effects and surgeons as random intercepts. The causal difference in probability of a successful outcome (estimand of interest) is calculated using Monte Carlo simulation with bootstrapping for confidence intervals. Packages for estimation within standard statistical software are reviewed briefly. A step by step application of methods is illustrated using the Amaze randomised trial of ablation as an adjunct to cardiac surgery in patients with irregular heart rhythm, with a co-intervention (removal of the left atrial appendage) administered to a subset of participants at the surgeon's discretion. The primary outcome was return to normal heart rhythm at one year post surgery. RESULTS: In Amaze, 17% (95% confidence interval: 6%, 28%) more patients in the active arm had a successful outcome, but there was a large difference between active and control arms in the proportion of patients who received the co-intervention (55% and 30%, respectively). Causal mediation analysis suggested that around 1% of the treatment effect was attributable to the co-intervention (16% natural direct effect). The controlled direct effect ranged from 18% (6%, 30%) if the co-intervention were mandated, to 14% (2%, 25%) if it were prohibited. Including age as a moderator of the mediation effects showed that the natural direct effect of ablation appeared to decrease with age. CONCLUSIONS: Causal mediation analysis is a useful quantitative tool to explore mediating effects of co-interventions in surgical trials. In Amaze, investigators could be reassured that the effect of the active treatment, not explainable by differential use of the co-intervention, was significant across analyses

Surgical treatments compared with early structured physiotherapy in secondary care for adults with primary frozen shoulder: the UK FROST three-arm RCT

Background Frozen shoulder causes pain and stiffness. It affects around 10% of people in their fifties and is slightly more common in women. Costly and invasive surgical interventions are used, without high-quality evidence that these are effective. Objectives To compare the clinical effectiveness and cost-effectiveness of three treatments in secondary care for adults with frozen shoulder; to qualitatively explore the acceptability of these treatments to patients and health-care professionals; and to update a systematic review to explore the trial findings in the context of existing evidence for the three treatments. Design This was a pragmatic, parallel-group, multicentre, open-label, three-arm, randomised superiority trial with unequal allocation (2 : 2 : 1). An economic evaluation and a nested qualitative study were also carried out. Setting The orthopaedic departments of 35 hospitals across the UK were recruited from April 2015, with final follow-up in December 2018. Participants Participants were adults (aged ≥ 18 years) with unilateral frozen shoulder, characterised by restriction of passive external rotation in the affected shoulder to < 50% of the opposite shoulder, and with plain radiographs excluding other pathology. Interventions The inventions were early structured physiotherapy with a steroid injection, manipulation under anaesthesia with a steroid injection and arthroscopic capsular release followed by manipulation. Both of the surgical interventions were followed with post-procedural physiotherapy. Main outcome measures The primary outcome and end point was the Oxford Shoulder Score at 12 months post randomisation. A difference of 5 points between early structured physiotherapy and manipulation under anaesthesia or arthroscopic capsular release or of 4 points between manipulation under anaesthesia and arthroscopic capsular release was judged clinically important. Results The mean age of the 503 participants was 54 years; 319 were female (63%) and 150 had diabetes (30%). The primary analyses comprised 473 participants (94%). At the primary end point of 12 months, participants randomised to arthroscopic capsular release had, on average, a statistically significantly higher (better) Oxford Shoulder Score than those randomised to manipulation under anaesthesia (2.01 points, 95% confidence interval 0.10 to 3.91 points; p = 0.04) or early structured physiotherapy (3.06 points, 95% confidence interval 0.71 to 5.41 points; p = 0.01). Manipulation under anaesthesia did not result in statistically significantly better Oxford Shoulder Score than early structured physiotherapy (1.05 points, 95% confidence interval –1.28 to 3.39 points; p = 0.38). No differences were deemed of clinical importance. Serious adverse events were rare but occurred in participants randomised to surgery (arthroscopic capsular release, n = 8; manipulation under anaesthesia, n = 2). There was, however, one serious adverse event in a participant who received non-trial physiotherapy. The base-case economic analysis showed that manipulation under anaesthesia was more expensive than early structured physiotherapy, with slightly better utilities. The incremental cost-effectiveness ratio for manipulation under anaesthesia was £6984 per additional quality-adjusted life-year, and this intervention was probably 86% cost-effective at the threshold of £20,000 per quality-adjusted life-year. Arthroscopic capsular release was more costly than early structured physiotherapy and manipulation under anaesthesia, with no statistically significant benefit in utilities. Participants in the qualitative study wanted early medical help and a quicker pathway to resolve their shoulder problem. Nine studies were identified from the updated systematic review, including UK FROST, of which only two could be pooled, and found that arthroscopic capsular release was more effective than physiotherapy in the long-term shoulder functioning of patients, but not to the clinically important magnitude used in UK FROST. Limitations Implementing physiotherapy to the trial standard in clinical practice might prove challenging but could avoid theatre use and post-procedural physiotherapy. There are potential confounding effects of waiting times in the trial. Conclusions None of the three interventions was clearly superior. Early structured physiotherapy with a steroid injection is an accessible and low-cost option. Manipulation under anaesthesia is the most cost-effective option. Arthroscopic capsular release carries higher risks and higher costs. Future work Evaluation in a randomised controlled trial is recommended to address the increasing popularity of hydrodilatation despite the paucity of high-quality evidence. Trial registration Current Controlled Trials ISRCTN48804508. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 71. See the NIHR Journals Library website for further project information

Effectiveness of interventions for the management of primary frozen shoulder: A systematic review of randomised trials

AimsThis systematic review places a recently completed multi-centre randomised controlled trial (RCT) UK FROST, in the context of existing randomised evidence for the management of primary frozen shoulder. UK FROST compared the effectiveness of pre-specified physiotherapy techniques with a steroid injection (PTSI), manipulation under anaesthesia (MUA) with a steroid injection and arthroscopic capsular release (ACR). This review updates a 2012 review focusing on the effectiveness of MUA, ACR, hydrodilatation, and PTSI. MethodsMEDLINE, Embase, PEDro, Science Citation Index, Clinicaltrials.gov, CENTRAL and WHO International Clinical Trials Registry were searched up-to December 2018. Reference lists of included studies were screened. No language restrictions applied. Eligible studies were RCTs comparing the effectiveness of MUA, ACR, PTSI and hydrodilatation against each other or supportive care or no treatment for the management of primary frozen shoulder. ResultsNine RCTs were included. The primary outcome of patient reported shoulder function at long-term follow-up (>6 months and ≤ 12 months) was reported for five treatment comparisons across four studies. Standardised mean difference (SMD) were: ACR vs MUA: 0.21 (95% CI: 0.00 to 0.42), ACR vs supportive care: -0.13 (95% CI: -1.10 to 0.83), and ACR vs PTSI:0.33 (95% CI: 0.07 to 0.59) and 0.25 (95% CI: -0.34 to 0.85) all favouring ACR; MUA vs Supportive care: 0 (95% CI: -0.44 to 0.44) not favouring either; and MUA vs PTSI: 0.12 (95% CI: -0.14 to 0.37) favouring MUA. None of these differences met the threshold of clinical significance agreed for the UK FROST and most confidence intervals included zero. ConclusionThe findings from a recent multi-centre RCT provided the strongest evidence that, when compared with each other, neither PTSI, MUA nor ACR are clinically superior. Evidence from smaller RCTs did not change this conclusion. Hydrodilatation’s effectiveness based on four RCTs was inconclusive and remains an evidence gap. Where does this fit in the literature?•There were few high quality and adequately powered randomised studies that evaluated key treatment choices in the management of patients with primary frozen shoulder.•UK FROST has addressed this and provided the strongest evidence that when compared with each other neither PTSI, MUA nor ACR are clinically superior. Evidence from smaller RCTs did not change this conclusion.•There is an evidence gap suggesting the need for a rigorously designed and adequately powered RCT to evaluate the comparative effectiveness of hydrodilatation

friendship groups research study: pilot randomised controlled trial

Background: Loneliness in older people is associated with poor health-related quality of life (HRQoL). We undertook a parallel-group randomised controlled trial to evaluate the effectiveness and cost-effectiveness of telephone befriending for the maintenance of HRQoL in older people. An internal pilot tested the feasibility of the trial and intervention. Methods: Participants aged>74 years, with good cognitive function, living independently in one UK city were recruited through general practices and other sources, then randomised to: (1) 6 weeks of short one-to-one telephone calls, followed by 12 weeks of group telephone calls with up to six participants, led by a trained volunteer facilitator; or (2) a control group. The main trial required the recruitment of 248 participants in a 1-year accrual window, of whom 124 were to receive telephone befriending. The pilot specified three success criteria which had to be met in order to progress the main trial to completion: recruitment of 68 participants in 95 days; retention of 80 % participants at 6 months; successful delivery of telephone befriending by local franchise of national charity. The primary clinical outcome was the Short Form (36) Health Instrument (SF-36) Mental Health (MH) dimension score collected by telephone 6 months following randomisation. Results: We informed 9,579 older people about the study. Seventy consenting participants were randomised t

Additional file 2: of Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Hydrotherapy manual. (PDF 136 kb

Additional file 1: of Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

CONSORT. (DOCX 24 kb